Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax

Ueda, Masashi; Li, Shimo; Itoh, Masanori; Hayakawa-Yano, Yoshika; Wang, Miao-xing; Hayakawa, Miki; Hasebe-Matsubara, Ryoko; Ohta, Kazunori; Ohta, Emi; Mizuno, Akihito; Hida, Yoko; Matsumoto, Munekazu; Chen, Huayue; Nakagawa, Toshiyuki

doi:10.1016/j.bbrc.2013.12.114

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Also, Koyano et al (2014) suggested that a cytoplasmic aggregation pattern of mutant ataxin-2 is prevalent in early stages of SCA2, whereas the presence of nuclear inclusions is related to a final stage. According to these and other studies (Ueda et al, 2014), the cytoplasmic ataxin-2 granules might be the first aggregated species in SCA2, actively contributing to pathogenesis by disrupting essential cell mechanisms. However, on an interesting note, the presence of aggregates in the cerebellar PCs remains quite controversial, with only a few reports of non-ubiquitinated cytoplasmic inclusions in mouse models (Huynh et al, 2000; Damrath et al, 2012).…”

Section: Disease Mechanisms Of Sca2mentioning

confidence: 65%

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

et al. 2016

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide.

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Section: Disease Mechanisms Of Sca2mentioning

confidence: 65%

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

et al. 2016

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“…Our data imply that on average, the severity of GCS serves as the most reliable predictor of neuronal survival. There are several lines of research indicating that distributed cytoplasmic polyQ protein can interfere with vital cell functions such as formation of the endoplasmatic reticulum and, interestingly, DNA repair . However, because of the limitations of human post‐mortem material we are unable to ascertain whether GCS itself represents the primary toxic aggregate type or if it is merely an indicator of underlying or downstream pathological events.…”

Section: Discussionmentioning

confidence: 99%

On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3

et al. 2016

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The polyglutamine (polyQ) diseases are a group of genetically and clinically heterogeneous neurodegenerative diseases, characterized by the expansion of polyQ sequences in unrelated disease proteins, which form different types of neuronal aggregates. The aim of this study was to characterize the aggregation pathology in the brainstem of spinocerebellar ataxia type 2 (SCA2) and 3 (SCA3) patients. For good recognition of neurodegeneration and rare aggregates, we employed 100 µm PEG embedded brainstem sections, which were immunostained with the 1C2 antibody, targeted at polyQ expansions, or with an antibody against p62, a reliable marker of protein aggregates. Brainstem areas were scored semiquantitatively for neurodegeneration, severity of granular cytoplasmic staining (GCS) and frequency of neuronal nuclear inclusions (NNI). SCA2 and SCA3 tissue exhibited the same aggregate types and similar staining patterns. Several brainstem areas showed statistically significant differences between disease groups, whereby SCA2 showed more severe GCS and SCA3 showed more numerous NNI. We observed a positive correlation between GCS severity and neurodegeneration in SCA2 and SCA3 and an inverse correlation between the frequency of NNI and neurodegeneration in SCA3. Although their respective disease proteins are unrelated, SCA2 and SCA3 showed the same aggregate types. Apparently, the polyQ sequence alone is sufficient as a driver of protein aggregation. This is then modified by protein context and intrinsic properties of neuronal populations. The severity of GCS was the best predictor of neurodegeneration in both disorders, while the inverse correlation of neurodegeneration and NNI in SCA3 tissue implies a protective role of these aggregates.

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“…This caspase is an effector that is found in the activated form of the microsomal fraction after apoptotic stimuli [53].…”

Section: Caspase-7 Apoptosis-related Cysteine Peptidase (Casp7)mentioning

confidence: 99%

Identification of common therapeutic targets for selected neurodegenerative disorders: An in silico approach

Ahmad

Baig

Gupta

et al. 2016

Journal of Computational Science

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Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax

Cited by 15 publications

References 26 publications

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3

Identification of common therapeutic targets for selected neurodegenerative disorders: An in silico approach

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